DESCRIPTION: Diabetic nephropathy is the major health problem in patients with IDDM. Recent clinical trials have shown that the natural history of diabetic nephropathy in IDDM can be modified by intervening at an early stage, microalbuminuria. Previous research supported by this grant provided strong evidence that the onset of microalbuminuria is determined by a different set of factors than its progression to overt proteinuria. This proposal explores this hypothesis and has the following goals: (1) To identify determinants of the onset of microalbuminuria: We will obtain frequent measurements of relevant exposures and of urinary albumin excretion (ACR) in our cohort of 787 IDDM patients with normoalbuminuria during an additional 5 years of followup. We will examine the relationship between the development of microalbuminuria and novel measures of hyperglycemia exposure, urinary levels of interleukin 6, and cigarette smoking. (2) To identify determinants of progression of microalbuminuria: We will obtain frequent measurements of ACR and will repeat biennial clinical and laboratory measurements in our cohort of 713 IDDM with microalbuminuria during the next 5 years of followup. We will use these new data to examine the relationship between progression of microalbuminuria and novel indices of lipid abnormalities, hyperfibrinogenemia, elevated blood pressure, and treatment with ACE inhibitors. (3) To identify genetic markers associated with the onset of microalbuminuria and its progression: We will collect DNA samples from available parents and IDDM individuals with (a) normoalbuminuria (n=400), (b) new onset microalbuminuria (n=200), (c) microalbuminuria and non-progression (n=400), and (d) microalbuminuria and progression to proteinuria (n=200). These DNA samples will be used to study eNOS, ACE, and ApoE, genes for which we have found linkage association and linkage with advanced nephropathy. We will test the hypothesis that polymorphisms in eNOS and ACE genes contribute to the onset of microalbuminuria and polymorphism in ApoE contributes to progression of microalbuminuria to overt proteinuria.